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Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke

Background: Increased inflammation activates blood coagulation system, higher platelet activation plays a key role in the pathophysiology of ischemic stroke (IS). During platelet activation and aggregation process, platelets may cause increased release of several proinflammatory, and prothrombotic m...

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Autores principales: Eyileten, Ceren, Jakubik, Daniel, Shahzadi, Andleeb, Gasecka, Aleksandra, van der Pol, Edwin, De Rosa, Salvatore, Siwik, Dominika, Gajewska, Magdalena, Mirowska-Guzel, Dagmara, Kurkowska-Jastrzebska, Iwona, Czlonkowska, Anna, Postula, Marek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102701/
https://www.ncbi.nlm.nih.gov/pubmed/35562921
http://dx.doi.org/10.3390/ijms23094530
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author Eyileten, Ceren
Jakubik, Daniel
Shahzadi, Andleeb
Gasecka, Aleksandra
van der Pol, Edwin
De Rosa, Salvatore
Siwik, Dominika
Gajewska, Magdalena
Mirowska-Guzel, Dagmara
Kurkowska-Jastrzebska, Iwona
Czlonkowska, Anna
Postula, Marek
author_facet Eyileten, Ceren
Jakubik, Daniel
Shahzadi, Andleeb
Gasecka, Aleksandra
van der Pol, Edwin
De Rosa, Salvatore
Siwik, Dominika
Gajewska, Magdalena
Mirowska-Guzel, Dagmara
Kurkowska-Jastrzebska, Iwona
Czlonkowska, Anna
Postula, Marek
author_sort Eyileten, Ceren
collection PubMed
description Background: Increased inflammation activates blood coagulation system, higher platelet activation plays a key role in the pathophysiology of ischemic stroke (IS). During platelet activation and aggregation process, platelets may cause increased release of several proinflammatory, and prothrombotic mediators, including microRNAs (miRNAs) and extracellular vesicles (EVs). In the current study we aimed to assess circulating miRNAs profile related to platelet function and inflammation and circulating EVs from platelets, leukocytes, and endothelial cells to analyse their diagnostic and predictive utility in patients with acute IS. Methods: The study population consisted of 28 patients with the diagnosis of the acute IS. The control group consisted of 35 age- and gender-matched patients on acetylsalicylic acid (ASA) therapy without history of stroke and/or TIA with established stable coronary artery disease (CAD) and concomitant cardiovascular risk factors. Venous blood samples were collected from the control group and patients with IS on ASA therapy (a) 24 h after onset of acute IS, (b) 7-days following index hospitalization. Flow cytometry was used to determine the concentration of circulating EVs subtypes (from platelets, leukocytes, and endothelial cells) in platelet-depleted plasma and qRT-PCR was used to determine several circulating plasma miRNAs (miR-19a-3p, miR-186-5p and let-7f). Results: Patients with high platelet reactivity (HPR, based on arachidonic acid-induced platelet aggregometry) had significantly elevated platelet-EVs (CD62+) and leukocyte-EVs (CD45+) concentration compared to patients with normal platelet reactivity at the day of 1 acute-stroke (p = 0.012, p = 0.002, respectively). Diagnostic values of baseline miRNAs and EVs were evaluated with receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for miR-19a-3p was 0.755 (95% CI, 0.63–0.88) p = 0.004, for let-7f, it was 0.874 (95% CI, 0.76–0.99) p = 0.0001; platelet-EVs was 0.776 (95% CI, 0.65–0.90) p = 0.001, whereas for leukocyte-EVs, it was 0.715 (95% CI, 0.57–0.87) p = 0.008. ROC curve showed that pooling the miR-19a-3p expressions, platelet-EVs, and leukocyte-EVs concentration yielded a higher AUC than the value of each individual biomarker as AUC was 0.893 (95% CI, 0.79–0.99). Patients with moderate stroke had significantly elevated miR-19a-3p expression levels compared to patients with minor stroke at the first day of IS. (AUC: 0.867, (95% CI, 0.74–0.10) p = 0.001). Conclusion: Combining different biomarkers of processes underlying IS pathophysiology might be beneficial for early diagnosis of ischemic events. Thus, we believe that in the future circulating biomarkers might be used in the prehospital phase of IS. In particular, circulating plasma EVs and non-coding RNAs including miRNAs are interesting candidates as bearers of circulating biomarkers due to their high stability in the blood and making them highly relevant biomarkers for IS diagnostics.
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spelling pubmed-91027012022-05-14 Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke Eyileten, Ceren Jakubik, Daniel Shahzadi, Andleeb Gasecka, Aleksandra van der Pol, Edwin De Rosa, Salvatore Siwik, Dominika Gajewska, Magdalena Mirowska-Guzel, Dagmara Kurkowska-Jastrzebska, Iwona Czlonkowska, Anna Postula, Marek Int J Mol Sci Article Background: Increased inflammation activates blood coagulation system, higher platelet activation plays a key role in the pathophysiology of ischemic stroke (IS). During platelet activation and aggregation process, platelets may cause increased release of several proinflammatory, and prothrombotic mediators, including microRNAs (miRNAs) and extracellular vesicles (EVs). In the current study we aimed to assess circulating miRNAs profile related to platelet function and inflammation and circulating EVs from platelets, leukocytes, and endothelial cells to analyse their diagnostic and predictive utility in patients with acute IS. Methods: The study population consisted of 28 patients with the diagnosis of the acute IS. The control group consisted of 35 age- and gender-matched patients on acetylsalicylic acid (ASA) therapy without history of stroke and/or TIA with established stable coronary artery disease (CAD) and concomitant cardiovascular risk factors. Venous blood samples were collected from the control group and patients with IS on ASA therapy (a) 24 h after onset of acute IS, (b) 7-days following index hospitalization. Flow cytometry was used to determine the concentration of circulating EVs subtypes (from platelets, leukocytes, and endothelial cells) in platelet-depleted plasma and qRT-PCR was used to determine several circulating plasma miRNAs (miR-19a-3p, miR-186-5p and let-7f). Results: Patients with high platelet reactivity (HPR, based on arachidonic acid-induced platelet aggregometry) had significantly elevated platelet-EVs (CD62+) and leukocyte-EVs (CD45+) concentration compared to patients with normal platelet reactivity at the day of 1 acute-stroke (p = 0.012, p = 0.002, respectively). Diagnostic values of baseline miRNAs and EVs were evaluated with receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for miR-19a-3p was 0.755 (95% CI, 0.63–0.88) p = 0.004, for let-7f, it was 0.874 (95% CI, 0.76–0.99) p = 0.0001; platelet-EVs was 0.776 (95% CI, 0.65–0.90) p = 0.001, whereas for leukocyte-EVs, it was 0.715 (95% CI, 0.57–0.87) p = 0.008. ROC curve showed that pooling the miR-19a-3p expressions, platelet-EVs, and leukocyte-EVs concentration yielded a higher AUC than the value of each individual biomarker as AUC was 0.893 (95% CI, 0.79–0.99). Patients with moderate stroke had significantly elevated miR-19a-3p expression levels compared to patients with minor stroke at the first day of IS. (AUC: 0.867, (95% CI, 0.74–0.10) p = 0.001). Conclusion: Combining different biomarkers of processes underlying IS pathophysiology might be beneficial for early diagnosis of ischemic events. Thus, we believe that in the future circulating biomarkers might be used in the prehospital phase of IS. In particular, circulating plasma EVs and non-coding RNAs including miRNAs are interesting candidates as bearers of circulating biomarkers due to their high stability in the blood and making them highly relevant biomarkers for IS diagnostics. MDPI 2022-04-20 /pmc/articles/PMC9102701/ /pubmed/35562921 http://dx.doi.org/10.3390/ijms23094530 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Eyileten, Ceren
Jakubik, Daniel
Shahzadi, Andleeb
Gasecka, Aleksandra
van der Pol, Edwin
De Rosa, Salvatore
Siwik, Dominika
Gajewska, Magdalena
Mirowska-Guzel, Dagmara
Kurkowska-Jastrzebska, Iwona
Czlonkowska, Anna
Postula, Marek
Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke
title Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke
title_full Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke
title_fullStr Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke
title_full_unstemmed Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke
title_short Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke
title_sort diagnostic performance of circulating mirnas and extracellular vesicles in acute ischemic stroke
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102701/
https://www.ncbi.nlm.nih.gov/pubmed/35562921
http://dx.doi.org/10.3390/ijms23094530
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